Vertebral bone quality is essential in vertebral strength. A major factor of bone quality is the bone mineral density and its distribution throughout the bone and several evidences now show that bone mineral density impacts several human conditions.
Osteoporosis, or porous bone, is a disease characterized by low bone mineral density, leading to bone fragility and an increased susceptibility to fractures, especially of the hip, spine and wrist, although any bone can be affected. If not prevented or if left untreated, osteoporosis can progress painlessly until a bone breaks. It is estimated that Osteoporosis is responsible for more than 1.5 million fractures annually, including over 300,000 hip fractures; and approximately 700,000 vertebral fractures; 250,000 wrist fractures; and 300,000 fractures at other sites. Genetic factors play an important role in the pathogenesis of osteoporosis and several studies suggest that between 50%-85% of the variance in bone mineral density is genetically determined (Gueguen et al. 1995; Arden and Spector 1997). However the genes responsible for these effects are incompletely defined. Most agents used to treat osteoporosis, such as estrogens and bisphosphonates, are not very effective. These agents retard bone resorption but do not improve connectivity. Therefore there is a permanent need to provide new targets for the treatment of osteoporosis.
A contrario, bone mineral density has been shown to be increased in several other pathologies or conditions. For example, increased bone mineral density has been shown in postmenopausal females with postthyroidectomy hypoparathyroidism. Moreover, several drugs have been shown to induce increased bone mineral density. For example, twelve month results from a Phase IIB study with odanacatib, (formerly MK-0822), an investigational selective inhibitor of cathespin-K, demonstrated dose-dependent increases in bone mineral density and reduced bone turnover compared to placebo in postmenopausal women (29th Annual Meeting of the American Society for Bone and Mineral Research (ASBMR)). Another example includes the Ghosal hematodiaphyseal dysplasia syndrome (GHDD) which is a rare autosomal recessive disorder characterized by increased bone mineral density with predominant diaphyseal involvement, aregenerative corticosensitive anemia and chronic biological inflammation (Ghosal et al. 1988).
Therefore, there is an existing need to identify factors which impact the bone mineral density so as to envisage methods for diagnosing, predicting, preventing and treating bone mineral density related diseases.
A wide variety of candidate genes have been studied so far in relation to bone mineral density, including the vitamin D receptor (Kelly P J et al. 1997) and the estrogen receptor (Kobayashi et al. 1996). Current evidence suggests that allelic variation in these genes accounts for only a small portion of the variance in bone mineral density however (Rubin et al. 1999) indicating that most of the genes which regulate bone mineral density remain to be discovered. The identification and genotyping of polymorphisms associated with regulation of bone mineral density is useful, to define markers of bone mass and hence, for example, susceptibility to bone mineral density related diseases.